The present invention relates to a process for the preparation of 7-[D(-)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephe m-4-carboxylic acid monohydrate.
7-[D(-)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem -4-carboxylic acid is an orally active semisynthetic cephalosporin known by its international non-proprietary name (INN) as "cefadroxil". Belgian patent No. 853,974 discloses the monohydrate of 7-[D(-)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephe m-4-carboxylic acid, hereinafter designated "cefadroxil monohydrate", having the formula: ##STR1## Cefadroxil monohydrate has the advantage of being a stable form of cefadroxil particularly useful in pharmaceutical formulations.
According to the Belgian patent, cefadroxil monohydrate is prepared by a process comprising:
(a) silylating 7-amino-3-desacetoxycephalosporanic acid in a substantially anhydrous aprotic solvent; PA1 (b) acylating the thus obtained silylated 7-amino-3-desacetotoxycephalosporanic acid with D(-)-.alpha.-amino-.alpha.-(p-hydroxyphenyl)acetylchloride hydrochloride in a substantially anhydrous aprotic solvent in the presence of an acid acceptor; PA1 (c) removing the silyl radicals by hydrolysis or alcoholysis of the acylation product of step (b); and PA1 (d) forming the desired monohydrate I either by bringing the solution pH to a higher value and forming a solvate with dimethylformamide, from which cefadroxil monohydrate is thereafter isolated; or (2) or by raising the pH of the solution and isolating the product by treatment with water. PA1 (a) 7-[D(-)-.alpha.-benzyloxycarbonylamino-.alpha.-(p-hydroxyphenyl)acetamido] -3-methyl-3-cephem-4-carboxylic acid of the formula: ##STR2## is solubilized in an organic solvent, in which no solvates are formed with cefadroxil, through silylation or salification with an organic base; PA1 (b) the thus obtained solution is subjected to catalytic hydrogenolysis; and, after removal of the catalyst, PA1 (c) the cefadroxil monohydrate is isolated through precipitation with water at a pH of about 4, and filtration.